Rapamycin enhances BCG-specific 3δT cells during intravesical BCG therapy for non-muscle invasive bladder cancer: A randomized, double-blind study

Niannian Ji, Neelam Mukherjee, Ryan M. Reyes, Jonathan Gelfond, Martin Javors, Joshua J. Meeks, David J. McConkey, Zhen Ju Shu, Chethan Ramamurthy, Ryan Dennett, Tyler J. Curiel, Robert S. Svatek

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1 Scopus citations

Abstract

Background Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of 3δT cells, which are critical for BCG's antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC. Methods A randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific 3δT cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires. Results Thirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1-2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific 3δT cells from baseline per group was as follows:-26% (-51% to 24%) for placebo, 9.6% (-59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (-31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary 3δT cells at the first week of BCG (p=0.02). Conclusions Four weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific 3δT cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-Term rapamycin safety, tolerability and effects on BCG efficacy.

Original languageEnglish (US)
Article numbere001941
JournalJournal for ImmunoTherapy of Cancer
Volume9
Issue number3
DOIs
StatePublished - Mar 2 2021

Keywords

  • immunity
  • immunotherapy
  • innate
  • urinary bladder neoplasms

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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